Key Concepts of Section 12.4

• By the end of the citric acid cycle (stage II), much of the energy originally present in the covalent bonds of glucose and fatty acids has been converted into high-energy electrons in the reduced coenzymes NADH and FADH₂. The energy from these electrons is used to generate the proton-motive force.

• In the mitochondrion, the proton-motive force is generated by coupling electron flow (from NADH and FADH₂ to O₂) to the energetically uphill transport of protons from the matrix across the inner membrane to the intermembrane space. This process, together with the synthesis of ATP from ADP and P_i driven by the proton-motive force, is called oxidative phosphorylation.

• As electrons flow from FADH₂ and NADH to O₂, they pass through multiprotein complexes. The four major complexes are NADH-CoQ reductase (complex I), succinate-CoQ reductase (complex II), CoQH₂–cytochrome c reductase (complex III), and cytochrome c oxidase (complex IV) (see Figure 12-22).

  551

• Each complex contains one or more electron-carrying prosthetic groups, which include iron-sulfur clusters, flavins, heme groups, and copper ions (see Table 12-4). Cytochrome c, which contains heme, and coenzyme Q (CoQ), a lipid-soluble small molecule, are mobile carriers that shuttle electrons between the complexes.

• Complexes I, III, and IV pump protons from the matrix into the intermembrane space. Complexes I and II reduce CoQ to CoQH₂, which carries protons and high-energy electrons to complex III. The heme protein cytochrome c carries electrons from complex III to complex IV, which uses them to pump protons and reduce molecular oxygen to water.

• The high-energy electrons from NADH enter the electron-transport chain through complex I, whereas the high-energy electrons from FADH₂ (derived from succinate in the citric acid cycle) enter the electron-transport chain through complex II. Additional electrons derived from FADH₂ by the initial step of fatty acyl–CoA β-oxidation increase the supply of CoQH₂ available for electron transport.

• The Q cycle allows four protons to be translocated per pair of electrons moving through complex III (see Figure 12-24).

• Each electron carrier in the chain accepts an electron or electron pair from a carrier with a less positive reduction potential and transfers the electron to a carrier with a more positive reduction potential. Thus the reduction potentials of electron carriers favor unidirectional, “downhill,” electron flow from NADH and FADH₂ to O₂ (see Figure 12-25).

• Within the inner mitochondrial membrane, electron-transport complexes assemble into supercomplexes held together by cardiolipin, a specialized phospholipid. Supercomplex formation may enhance the speed and efficiency of generation of the proton-motive force or play other roles.

• Reactive oxygen species (ROS) are toxic by-products of the electron-transport chain that can modify and damage proteins, DNA, and lipids. Specific enzymes (e.g., glutathione peroxidase, catalase) and small-molecule antioxidants (e.g., vitamin E) help protect against ROS-induced damage (see Figure 12-27). ROS can also be used as intracellular signaling molecules.

• A total of 10 H⁺ ions are translocated from the matrix across the inner membrane per electron pair flowing from NADH to O₂ (see Figure 12-22), whereas 6 H⁺ ions are translocated per electron pair flowing from FADH₂ to O₂.

• The proton-motive force is largely due to a voltage gradient across the inner membrane produced by proton pumping; the pH gradient plays a quantitatively less important role.